Thyroid hormones (TH), triiodothyronine (T3) and thyroxine (T4), play crucial roles in regulating cellular processes such as proliferation and metabolism, through binding to their cognate thyroid hormone receptors THRα and THRβ. THR's form homodimers or heterodimers with retinoid X receptors; when bound by TH, they act as classical transcription factors by binding to the promoter regions of target gene (FIG. 1).
Thyroid hormones are endogenous modulators of malignant tumors, including breast tumors. Indeed, increased thyroid hormone expression was positively correlated with overall breast cancer risk. While THRα is expressed in diverse normal and malignant tissues, little is known about its clinical relevance and specifically the relevance of alternatively spliced THRα isoforms, THRα1 and THRα2, in breast cancer. THRα1 binds to the thyroid hormone and mediates its biological effects, but THRα2 lacks the binding site for thyroid hormone and consequently functions as a weak antagonist of thyroid hormone signaling (FIG. 2).
Women whose tumors had high expression of THRα2 lived longer and had fewer breast cancer recurrences than those with low expression, particularly when THRα1 expression was concomitantly low [1]. This suggests that THRα2 may be protective and that THRα1 may be detrimental for breast cancer recurrence and survival. Biological rationale supports a differential effect of THRα1 and THRα2 expression on clinical outcomes. When THRα1 binds TH, it mediates transcription and expression of target genes [2, 3]. THRα2, on the other hand, is unable to bind TH because it lacks a ligand-binding domain [4-8]. Hence, it acts a constitutive transcriptional repressor and it may reduce the expression of p53, retinoblastoma and other growth-promoting genes in breast cancer [9].
Similar to reduction of estradiol levels in estrogen receptor (ER) positive breast cancers, it is conceivable that lowering TH levels may be therapeutic in THR-expressing cancers. Given their indispensable and life-sustaining roles, however, patients are unlikely to tolerate marked reductions in TH levels [6].